Autoimmune diseases are characterized by pathogenic immunological responses to autoantibodies. For example, autoimmune mechanisms are recognized as being factors in rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, Hashimoto""s disease, Addison""s disease, psoriasis, pernicious anemia, and multiple sclerosis.
Rheumatoid arthritis (RA) is a chronic systemic autoimmune inflammatory disorder characterized by potentially deforming polyarthritis (1-3). Estimates are that seven million people are afflicted with RA, of whom 1.4 million have definite RA by the American Rheumatology Association (ARA) diagnostic criteria (4). Definite RA is two to three times more frequent in females than in males in the U.S., with the prevalence of the disease increasing with advancing age (5).
The chronic phase of RA is marked by infiltration into the synovium of inflammatory cells and the proliferation of synovial mesenchymal cells (6). The synovium is frequently filled with mononuclear cells, a majority of which are of the helper/inducer T cell subpopulation. Numerous B lymphocytes and plasma cells are also present. The resultant immunoglobulin production from this cell mosaic is predominantly of the IgG isotype (30-60%), as well as IgM (10-30%). The majority of both isotypes is anti-IgG Fc or rheumatoid factor (RF). Immune complexes of the RF type can self-associate and activate or enhance local inflammation, leading to bone erosion and resorption.
Most patients with RA remain on a given therapy for only one to two years (7). The traditional approach to treatment has been to begin patient therapy with aspirin. If this treatment is not effective, patients are then treated with other non-steroidal anti-inflammatory drugs (NSAIDS). If this regimen fails to control the disease""s symptoms, then a more aggressive therapy using the xe2x80x9cslow-actingxe2x80x9d (SAARDS) or xe2x80x9cdisease-modifyingxe2x80x9d (DMARDS) drugs, i.e., hydroxychloroquine, intramuscular gold, or D-penicillamine, can be tried. If toxicity or limited effectiveness is seen, the more aggressive and lymphocytotoxic second-line agent azathioprine is administered, followed by methotrexate, and/or cyclophosphamide. Corticosteroids have been used as combination therapy with any of the drugs mentioned above when therapeutic effectiveness is limited.
Recently, many physicians have suggested the use of methotrexate before the use of intramuscular gold or hydroxychloroquine on patients refractory to aspirin but prior to the onset of joint damage. Studies are continuing, however, because the chronic administration of methotrexate results in possible renal toxicity. Furthermore, once the patient begins taking the anti-folate methotrexate, he must continue the drug indefinitely. Those taken off the drug are prone to xe2x80x9cflare-upxe2x80x9d of the disease. Therefore, an immunosuppressive anti-rheumatic drug with significantly lower toxicity is needed which could be used for longer periods of time.
The potent immunosuppressive drug cyclosporin A (CsA) has recently been used on refractory RA patients, but its usage may be limited due to its nephrotoxicity (8). Other immunotherapies are also being considered, such as monoclonal antibodies, cytokines, and MHC-binding peptides (9). However, at this time, none of the currently available therapies are entirely satisfactory, because of toxicities, opportunistic infections, etc. Drugs with little toxicity at effective doses over long-term use are greatly needed for treatment of autoimmune disease, particularly RA.
The present invention provides a method of treating autoimmune disease or preventing or ameliorating its symptoms, comprising administering to a patient in need of such treatment an effective amount of fludarabine-5xe2x80x2-monophosphate. In a preferred embodiment, the disease is rheumatoid arthritis.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.